Copper peptide GHK-Cu

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Copper peptide GHK-Cu

Tripeptide
Names
IUPAC name
6-Amino-2-[[2-[(2-aminoacetyl)amino]-3-(1H-imidazol-5-yl)propanoyl]amino]hexanoic acid
Other names
Glycyl-L-Histidyl-L-Lysine; Growth-modulating peptide; Kollaren; Liver cell growth factor; Liver growth factor Cu-GHK; Glycyl-histidyl-lysine, monocopper salt
Identifiers
3D model (
JSmol
)
UNII
  • O=C(N[C@@H](CC1=CN=CN1)C(N[C@@H](CCCCN)C(O)=O)=O)CN
Properties
C14H24N6O4
C14H22CuN6O4 (Cu complex)
Molar mass 340.38 g/mol
130.98 g/L [1]
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
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Copper peptide GHK-Cu is a naturally occurring copper complex of the tripeptide glycyl-L-histidyl-L-lysine. The tripeptide has strong affinity for copper(II) and was first isolated from human plasma. It can be found also in saliva and urine.

Overview

Several copper(II)-peptide complexes occur naturally.

anti-aging ingredient.[3]

History

Loren Pickart (1938-2023) isolated the copper peptide GHK-Cu from human plasma

chelating metal ions.[7]

In 1977, the growth modulating peptide was shown to be a glycyl-L-histidyl-L-lysine.[8] It is proposed that GHK-Cu modulates copper intake into cells.[9]

Wound healing

Biochemical studies

In the late 1980s, copper peptide GHK-Cu started attracting attention as a promising

glycosaminoglycans (in a biphasic curve) and DNA in the dermal wounds in rats. They also found out that the GHK sequence is present in collagen and suggested that the GHK peptide is released after tissue injury.[10][11] They proposed a class of emergency response molecules which are released from the extracellular matrix at the site of an injury.[12]
GHK-Cu also increased synthesis of decorin – a small proteoglycan involved in the regulation of collagen synthesis, wound healing regulation and anti-tumor defense.[13]

It was also established that GHK-Cu stimulates both the synthesis of

metalloproteinases, the enzymes which break down dermal proteins, and their inhibitors (anti-proteases). The fact that GHK-Cu not only stimulates the production of dermal components, but also regulates their breakdown suggests that it should be used with caution.[14]

Wound healing in animals

A series of animal experiments established pronounced wound healing activity of GHK-Cu. In the dermal wounds of rabbits GHK-Cu facilitated wound healing, causing better wound contraction, faster development of granular tissue and improved

enzymes.[15][16]

GHK-Cu has been found to induce a systemic enhancement of healing in rats, mice, and pigs; that is, the GHK-Cu peptide injected in one area of the body (such as the thigh muscles) improved healing at distant body areas (such as the ears). These treatments strongly increased healing parameters such as collagen production, angiogenesis, and wound closure in both wound chambers and full thickness wounds.

tumor necrosis factor alpha and elastin-degrading matrix metalloproteinases.[18]

Biotinylated GHK-Cu was incorporated into a collagen membrane, which was used as a wound dressing. This GHK-Cu enriched material stimulated wound contraction and

tumor necrosis factor-beta (a major inflammatory cytokine) compared with vehicle alone or with untreated wounds.[18]

Cosmetic use

Copper peptide GHK-Cu is widely used in

anti-wrinkle activity of copper peptide GHK-Cu.[21]

Biological chemistry

Copper binding

Replacement of

cellular receptor. The ability of GHK to interact both with copper and with a cellular receptor may allows it to transfer copper into and from cells. The small size of GHK permits speedy traveling in extracellular space and its easy access to cellular receptors.[22]

The molecular structure of the GHK copper complex (GHK-Cu) has been determined by X-ray crystallography, EPR spectroscopy, X-ray absorption spectroscopy, NMR spectroscopy, as well as other methods such as titration. In the GHK-Cu complex, the Cu (II) ion is coordinated by the nitrogen from the imidazole side chain of the histidine, another nitrogen from the alpha-amino group of glycine and the deprotonated amide nitrogen of the glycine–histidine peptide bond. Since such a structure could not explain a high stability constant of the GHK-Cu complex (log 10 =16.44 vs. 8.68 of the GH copper complex, which is similar to the GHK-Cu structure), it was proposed that another amino group participates in the complex formation. Cu(II) is also coordinated by the oxygen from the carboxyl group of the lysine from the neighboring complex. Another carboxyl group of lysine from a neighboring complex provides the apical oxygen, resulting in the square-planar pyramid configuration.[23] Many researchers proposed that at the physiological pH, GHK-Cu complexes can form binary and ternary structures which may involve amino acid histidine and/or the copper binding region of the albumin molecule. Lau and Sarkar found also that GHK can easily obtain copper 2+ bound to other molecules such as the high affinity copper transport site on plasma albumin (albumin binding constant log 10 =16.2 vs. GHK binding constant 16 log 10 =16.44). It has been established that copper (II) redox activity is silenced when copper ions are complexed with the GHK tripeptide, which allows the delivery of non-toxic copper into the cell.[24]

Biological significance

Copper is vital for all

eukaryotic organisms from microbes to humans. A dozen enzymes (cuproenzymes) use changes in copper oxidation state to catalyze important biochemical reactions including cellular respiration (cytochrome c oxidase), antioxidant defense (ceruloplasmin, superoxide dismutase (SOD), detoxification (metallothioneins), blood clotting (blood clotting factors V and VIII), melanin production (tyrosinase) and the connective tissue formation (lysyl peroxidase). Copper is required for iron metabolism, oxygenation, neurotransmission, embryonic development and many other essential biological processes. Another function of copper is signaling – for example, stem cells require a certain level of copper in the media to start their differentiation into cells needed for repair. Thus, GHK-Cu's ability to bind copper and to modulate its tissue level is a key factor determining its biological activity.[25]

References

  1. ^ "Archived copy" (PDF). Archived from the original (PDF) on 2012-03-24. Retrieved 2011-05-15.{{cite web}}: CS1 maint: archived copy as title (link)
  2. ^ "The Magic of Copper Peptides Science". Archived from the original on 2013-01-19. Retrieved 2012-05-16.
  3. S2CID 9354138
    .
  4. ^ Pickart, L; Thaler, MM (1973). "Tripeptide in human serum which prolongs survival of normal liver cells and stimulates growth in neoplastic liver". Nature New Biology. 243 (124): 85–87.
    PMID 4349963
    .
  5. PMID 5642099
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  6. PMID 20383582
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  7. ^ Pickart, L (1973), A tripeptide in human plasma that increases the survival of hepatocytes and the growth of hepatoma cells, Ph.D. Thesis in Biochemistry: University of California, San Francisco
  8. S2CID 29422959
    .
  9. S2CID 4304271
    .
  10. S2CID 19289897
    .
  11. PMID 1522753
    .
  12. PMID 15781322
    .
  13. PMID 11121126
    .
  14. PMID 11045606
    .
  15. PMID 18177285
    .
  16. PMID 17083573
    .
  17. ^ Pickart L. Compositions for accelerating wound healing in mammals containing cupric salt or complexes with amino acid or peptide. US Patent 5,164,367, 1992.
  18. ^
    PMID 14648529.{{cite journal}}: CS1 maint: multiple names: authors list (link
    )
  19. PMID 17049946
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  20. S2CID 205584531
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  21. PMID 29986520
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  22. PMID 11325542
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  23. PMID 21780203
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  24. PMID 7340824
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  25. ^ Pickart L. The human tripeptide GHK (Glycyl-L-histidyl-L-Lysine), the copper switch and the treatment of the degenerative conditions of aging. In Anti-Aging Therapeutics Volume XI, 301-3012. Ed. By Klatz R. and Goldman R. Chicago, IL, USA: American Academy of Medicine, 2009
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